Researchers have discovered tiny deposits of elemental copper and iron in the brains of two deceased Alzheimer’s patients. The metals were found in the nuclei of amyloid plaques, misfolded proteins, the accumulation of which is typical for Alzheimer’s disease. Charged iron and copper ions are found in numerous enzymes and proteins in the brain even in healthy people. However, the detection of elementary metal particles in connection with Alzheimer’s is new. He raises the question of how these metallic nanoparticles are formed and what influence they have on neurodegenerative diseases.
Iron and copper ions play an important role in the normal functioning of the brain: many enzymes and proteins contain the positively charged metal particles that, through reactions with other substances, are involved in the production of messenger substances in the brain, for example. Until now, it was assumed that the metals are always present in charged form, i.e. as ions, for example as iron oxide or copper oxide. They can assume different states of charge: Copper ions can be monovalent or bivalent (Cu+ and Cu2+), Iron ions bivalent or trivalent (Fe2+ and Fe3+). The balance between the differently charged ions is important for healthy brain chemistry. Earlier studies have already shown that a shift in the ratio may be related to the formation of amyloid plaques that are typical of Alzheimer’s.
Elemental metal in amyloid plaques
A team led by James Everett from Keele University in Great Britain has now investigated the distribution and chemical state of metals in the brains of Alzheimer’s patients. To do this, the researchers analyzed amyloid plaque cores that they had taken from the frontal and temporal lobes of two deceased Alzheimer’s patients. Under the X-ray microscope, the researchers detected various ionized forms of iron and copper within the plaques – and, to their surprise, also discovered nanoparticles of the metals in their elementary form.
“To the best of our knowledge, this is the first evidence of elemental metallic copper and iron in human tissue,” the researchers write. “This discovery raises fascinating new questions about the production and role of metal nanoparticles in the brain, such as whether their formation is related to neuropathological processes.” The researchers believe that the discovery could provide new insights into the origins of Alzheimer’s disease and related neurodegenerative diseases deliver.
Mechanisms not yet clarified
An important question is how the elementary metal particles came about. “There are various plausible explanations for this,” the researchers say. One possibility is that the protein beta-amyloid, from which the harmful plaques form, is responsible. Iron and copper ions bound to this protein could be chemically reduced directly. “In view of the high reduction potential of compounds made from copper and amyloid-beta compared to other complexes of copper with biomolecules, this is conceivable,” explain Everett and his colleagues. In fact, they were able to show that beta amyloid reduces divalent copper to monovalent. In this respect, the next step, the reduction from monovalent to elemental copper, would also be conceivable. Since monovalent copper is normally stabilized by oxygen, a lack of oxygen in the brain, as often occurs in neurodegenerative diseases, could promote further reduction.
Another possibility would be that enzymes are responsible for the process. “Various bacteria, fungi and plants produce elementary metallic nanoparticles, including those made from copper and iron,” the researchers report. “The mechanisms for these syntheses are not fully understood, but it is believed that they take place through enzymatic reduction, in some cases coupled with the oxidation of glucose.” Similar mechanisms could also be found in the human brain.
Danger or protection?
It is still unclear what role the elementary metallic nanoparticles play in the brain. Because they are particularly reactive, they could lead to the formation of reactive oxygen species that cause oxidative stress. “This could promote inflammatory processes in the brain and contribute to neuronal failure in the affected areas of the brain,” explain the researchers. On the other hand, the very fact that these particularly reactive metal particles become trapped in the amyloid plaques could be a mechanism to prevent their harmful effects on other brain structures. “The process of the formation and breakdown of amyloid plaques in the human brain, both in healthy individuals and in people with Alzheimer’s disease, needs further research,” the authors write.
Further knowledge in this area could one day lead to new treatment approaches. “Chemically reduced copper and iron, which is associated with amyloid structures, could represent an innovative target for alternative Alzheimer’s therapies that aim to reduce oxidative stress in affected brain regions,” the researchers speculate. “The discovery has the potential to redefine our understanding of the neurochemistry of metals and the role of metal toxicity in neurodegenerative diseases.”
Source: James Everett (Keele University, Staffordshire, UK) et al., Science Advances, doi: 10.1126 / sciadv.abf6707